Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[C:23]12([NH2:33])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[C:23]12([NH:33][C:20]([C:14]3[CH:13]=[N:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=4)[C:15]=3[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 63.1 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7) (160 mg, 0.5 mmol), 1-adamantylamine (76 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica 0-50% EtOAc/isohexane) to give the title compound as a colourless gum (143 mg, 63%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([CH3:21])[C:13]=2[N:14]=1.O1CCOCC1.[ClH:28]>>[Cl:28][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([CH3:21])[C:13]=2[N:14]=1
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(C#N)cc2[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1cc(C#N)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 80 °C

Procedure:
A suspension of 2-(4-iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile (1.8 g, 4.63 mmol) in 4 M HCl dioxane (40 mL) was heated to 80° C. for 6 h and cooled to room temperature. The precipitate was filtered and dried. The crude product (1.08 g, 82%) was used for the next step without purification. LRMS (neg. ESI, (M−H)−) m/z 283.
Reaction SMILES: C([S@]([NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1)=O)(C)(C)C.N[C@@H](C1C=CC=CC=1Cl)C1SC(NC(C2(C3C=CC4OCOC=4C=3)CC2)=O)=NC=1>CC#N>[NH2:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Agent: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl
Solvent: CC#N
Product: N[C@@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
(R)-N-(5-(Amino(2-chlorophenyl)-methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide was prepared from (R)-N-(5-((R)-t-butylsulfinylamino(2-chlorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide using the same protocol described for (S)-N-(5-(amino(2-chlorophenyl)-methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H), 7.33 (dd, J=7.9, 1.3 Hz, 1H), 7.27 (td, J=7.4, 1.5 Hz, 1H), 7.20 (td, J=7.6, 1.8 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 6.89 (td, J=8.2, 1.7 Hz, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.79 (s, 1H), 1.89 (s, 2H), 1.72-1.70 (m, 2H), 1,22-1.19 (m, 2H). HPLC ret. time 2.52 min, 10-99% CH3CN, 5 min run; ESI-MS 428.2 m/z (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:34][C:4]3[CH:5]=[CH:8][CH:9]=[CH:10][C:3]=3[C:2]([F:1])([F:11])[F:12])[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3C(F)(F)F)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 2-(trifluoromethyl)benzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61 (d, J=6.0, 1H), 7.93 (d, J=7.6, 0.5H), 7.85 (d, J=7.8, 0.5H), 7.63 (t, J=5.8, 3H), 7.53 (dd, J=7.9, 16.0, 1H), 7.38-7.23 (m, 5H), 4.36 (dd, J=5.7, 13.2, 1H), 3.76 (q, J=14.5, 1H), 3.66 (q, J=15.0, 1H), 3.23 (dd, J=2.2, 10.5, 1H), 3.03 (dd, J=2.2, 9.0, 0.5H), 2.69-2.60 (m, J=5.6, 17.6, 1H), 2.59-2.47 (m, 1H), 2.47-2.40 (m, J=10.2, 17.4, 1H), 2.39-2.12 (m, 3H), 1.96-1.82 (m, 1H), 1.78 (dt, J=6.2, 20.1, 0.5H), 1.68 (dt, J=7.2, 13.8, 0.5H), 1.48-1.24 (m, 1.5H), 1.20 (t, J=6.7, 3H), 0.70 (dd, J=1.7, 6.7, 3H); MS (ESI+) m/z 445 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:11][C:12](O)=[O:13])=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:3]=1.C1COCC1.C(Cl)(=O)C(Cl)=O.C[N:39](C=O)C>>[Cl:1][C:2]1[C:7]2[C:8]([CH2:11][C:12]([NH2:39])=[O:13])=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(N)=O)csc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of (4-chloro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetic acid (365 mg) and THF (dry) (5 mL) were added oxalyl chloride (0.095 mL) and DMF (6.98 μl) at room temperature. The mixture was stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (5 mL), and the solution was poured into stirred 28% aqueous ammonium hydroxide (5 mL) at room temperature. After stirring at room temperature for 15 min, the mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was crystallized from MeOH to give the title compound (320 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]C[CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17].CS(Cl)(=O)=O>>[C:16]([N:1]1[CH2:6][CH2:5][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:2]1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Agent: CS(=O)(=O)Cl
Product: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by substituting tert-butyl pyrrolidin-3-ylmethylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl chloride for methanesulfonyl chloride in EXAMPLE 147A.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[NH:13][CH:12]=2)=[C:6]([O:29][CH3:30])[CH:5]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:24]1([O:23][C:21]([NH:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][C:6]=2[O:29][CH3:30])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of 4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (0.82 grams, 1.95 mmol) in a 2:2:1 ratio of methanol:tetrahydrofuran:water (30 mL) was added lithium hydroxide monohydrate (0.41 grams, 0.73 mmol). The resulting solution was stirred for 12 hours at room temperature. The solution was concentrated, and the crude product treated with 1 hydrochloric acid (aq). The product was collected via filtration. Chromatography on silica gel (1:1 hexanes:ethyl acetate→5% methanol:methylene chloride) gave 4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.735 grams, 92 yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:26])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid (300 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (e).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH:26][CH3:27]>C(O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:26]([CH3:27])[CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Reactant: CNC
Solvent: CCO
Product: CN(C)C/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.18 g, 0.43 mmol) was treated with 33% dimethylamine in ethanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.018 g, 10%). MS (ES) m/z 379.8 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[CH2:3][NH2:4].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20](F)[C:19]=1[F:27])[CH3:14]>CS(C)=O>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:4][CH2:3][C:2]([F:1])([F:12])[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=2)[C:19]=1[F:27])[CH3:14]
Reactant: Cc1ccc(C(F)(F)CN)nc1
Reactant: CCOC(=O)Cc1c(C#N)ccc(F)c1F
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccc(C)cn2)c1F
Temperature: 90 °C
Reaction time: 20 h
Yield: 48.2 %

Procedure:
A mixture of 2,2-Difluoro-2-(5-methyl-pyridin-2-yl)-ethylamine (1.85 g, 10.76 mmol, 2×) and (6-Cyano-2,3-difluoro-phenyl)-acetic acid ethyl ester (1.2 g, 5.33 mmol), prepared as described in Example 2f, was dissolved into DMSO (3 mL) and heated to 90° C. under argon. After 20 h, the reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous phase was re-extracted with EtOAc (30 mL) and the combined organic phase dried over Na2SO4 and concentrated to afford a yellow oil. Purification via flash chromatography (20% EtOAc/hexanes) afforded the product as a clear oil (968 mg, 2.57 mmol, 48% yield). 1H NMR (300 Hz, CDCl3) δ 8.49 (s, 1H), 7.59 (m, 2H), 7.30 (m, 1H), 6.79 (t, J=8.2 Hz, 1H), 4.13 (m, 4H), 3.80 (d, J=2.0 Hz, 2H), 2.41 (s, 3H), 1.27 (t, J=6.9 Hz, 3H); LC/MS (m/z) [M+1]+ 378.0 (calculated for C19H19F3N3O2, 378.4).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH3:21])[C:2]#[CH:3].C(#N)C.C(N(CC)CC)C.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[C:33]1([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH3:21])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C#CCOCCCn1c(C)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1nc2cnc3ccccc3c2n1CCCOCC#Cc1ccccc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3-(2-methyl-1H-Imidazo[4,5-c]quinolin-1-yl)propyl (prop-2-ynyl) ether (4.6585 g, 16.68 mmol) from Part A, anhydrous acetonitrile (60 mL), anhydrous triethylamine (6 mL, 43.37 mmol), and iodobenzene (2.1 mL, 18.34 mmol) was heated to 80° C. with stirring. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.334 mmol), and copper(I) iodide (0.13 g, 0.667 mmol) were added and the mixture was allowed to stir for 0.5 hour. Analysis by HPLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography over silica gel, employing dichloromethane (1 L) and 98/2 dichloromethane/methanol as the eluants. The resulting green oil (5.1 g) was triturated with ether, but no solids formed. The oil was placed under high vacuum (4 torr) at room temperature. HNMR analysis of the resulting oil showed the presence of ether. The oil was further dried under high vacuum to provide 4.7 g of dark oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:13]N(N=O)C(N)=O.[OH-].[K+]>COCCOC.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:13])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Yield: 149.5 %

Procedure:
1.00 grams (6 millimoles) of m-nitrobenzoic acid and 2.4 grams (2.4 millimoles) of N-methyl,N-nitrosourea were dissolved in 25 milliliters of a 5:1 mixture of 1,2-dimethoxyethane and water. 40 milliliters of 0.6 N potassium hydroxide was added in a dropwise manner while the mixture was held at 0°C. in an ice bath. The solution was extracted with ether (4×50 milliliters) and the water layer (pH 10) was saved. The ether layer was dried (MgSO4) and workup gave 0.65 grams of methyl m-nitrobenzoate, melting point 71°-72°C. The water layer gave 0.25 grams of unreacted acid. Yield, based on consumed acid, was approximately 85 percent.
Reaction SMILES: [C:1]([CH:3]([N:14]([CH:21]1[CH2:26][CH2:25][C:24]([N:33]([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)#[N:2].[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O.C1(C)C=CC=CC=1>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH:3]([N:14]([CH:21]2[CH2:22][CH2:23][C:24]([N:33]([CH3:34])[CH3:35])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[C:1]2[NH:38][N:37]=[N:36][N:2]=2)=[CH:6]1
Reactant: CN(C)C1(c2ccccc2)CCC(N(C(=O)C(F)(F)F)C(C#N)Cc2c[nH]c3ccccc23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(N(C(=O)C(F)(F)F)C(Cc2c[nH]c3ccccc23)c2nnn[nH]2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of N-[1-cyano-2-(1H-indol-3-yl)ethyl]-N-(4-dimethylamino-4-phenylcyclohexyl)-2,2,2-trifluoroacetamide (polar diastereomer) (613 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) and toluol (5 mL) was mixed with sodium azide (825 mg, 12.7 mmol) and triethylamine hydrochloride (1.74 g, 12.7 mmol) and stirred for 2 d at 80° C. in a Teflon pressure vessel. The solvent was then concentrated to low volume in a vacuum, the residue repeatedly mixed with toluol and the solution again concentrated to low volume in a vacuum each time. The raw product (1.62 g) was purified by flash chromatography (200 g, 20×4; 1 cm) with dichloromethane/methanol [2:1+1% NH3 (32% in H2O)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:5]([C@@H:6]2[CH2:19][CH:18]=[CH:16][CH2:23][C@H:7]2[N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Reactant: Oc1ccc(O)cc1
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-nitrostyrene (compound J1), and 1.0 g (9.1 mmol) of hydroquinone are suspened in 200 ml of abs. toluene and treated at −70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred at 160° C. for 6 days in an autoclave and then cooled. Some of the solvent is removed on a rotary evaporator, and the resulting precipitate is filtered off with suction and recrystallized in ethanol. M.p.: 113.5-115.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][C:44]1([OH:47])[CH2:46][CH2:45]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:42][CH2:43][C:44]3([OH:47])[CH2:46][CH2:45]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCC1(O)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
To a mixture of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (735.7 mg, 1.52 mmol) and 2-(1-hydroxycyclopropyl)ethyl methanesulfonate (3.04 mmol) in 8 mL of N,N-dimethylacetamide was added cesium carbonate (4.955 g, 15.2 mmol). After stirring at 40° C. for 1 day, the reaction was quenched with water (5 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column (CH2Cl2/CH3OH (v/v)=45:1) to afford the title compound as a white solid (270 mg, 15.6%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6]1)=[O:4].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:1][CH2:2][C:3]([N:5]3[CH2:9][CH2:8][CH:7]([N:10]4[CH2:11][CH2:12][CH:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:14][CH2:15]4)[CH2:6]3)=[O:4])=[N:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(CNc1ncnc2cc(Cl)ccc12)N1CCC(N2CCC(c3ccccc3)CC2)C1
Yield: 58.9 %

Procedure:
A solution of 2-amino-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (preparation #9) (0.108 g, 0.377 mmol), 4,7-dichloroquinazoline (0.075 g, 0.377 mmol) and DIEA (0.1 mL, 0.565 mmol) in n-butanol was heated in a microwave (CEM Explorer, maximum power 300 W) at about 120° C. for about 20 min. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (20% to 50% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5, over 30 min at 81 mL/min; λ=254 nm; Microsorb C18, 100 Å, 5 μm, 250×46 mm column) to yield 2-(7-chloroquinazolin-4-ylamino)-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (0.100 g, 0.222 mmol) as a yellow solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 450.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH:12]1([C:15]([NH2:18])([CH3:17])[CH3:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:12]1([C:15]([NH:18][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)([CH3:17])[CH3:16])[CH2:14][CH2:13]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC(C)(N)C1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(NC(C)(C)C2CC2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (750 mg, 4.0 mmol) in DMF (8 mL) was added 2-cyclopropylpropan-2-amine (400 mg, 4.0 mmol) and DIEA (1560 mg, 12.0 mmol). The resulting mixture was stirred at 60° C. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (665 mg, 2.68 mmol, 66% yield) as a white solid. MS (ESI) m/z=249.2 [M+H]+.
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[C:13]([NH:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH3:30])[CH2:27][S:28](=[O:29])[C@H:23]12)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:13]([NH:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([O:33][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:32])=[C:26]([CH2:30][Br:36])[CH2:27][S:28](=[O:29])[C@H:23]12)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Solvent: c1ccccc1
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Yield: 56 %

Procedure:
375 mg (1.88 mmoles) of N-methyl-N-trimethylsilyltrifluoroacetamide were added to a suspension of 387.5 mg (1.16 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 40 ml of benzene at room temperature and after stirring at room temperature for half an hour, a clear, yellow solution was obtained. This was cooled to 5° C. and bromination was carried out in half an hour with 306.0 mg (1.72 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 56% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.